The long-term goal of this project is to identify and characterize the gene(s) responsible for interindividual differences in response to cadmium (Cd). Environmental Cd is absorbed by the small intestine and lung, is bound to metallothionein and glutathione in hepatocytes, and is deposited in the kidney. The kidney is the major target organ for human and lab animal Cd exposure. During the current funding period, we identified the Slc39a8 gene as the Cdm locus responsible for Cd-induced testicular necrosis. Slc39a8 encodes the ZIPS transporter protein, which we show is a high-affinity apically-oriented rogue Cd/HCO3- cotransporter. ZIPS expression in culture increases Cd influx and sensitizes (>30-fold) the cells to Cd. ZIPS is expressed in a cell-type-specific manner and is highest in alveolar and tubular epithelial cells in the lung and kidney, respect- tively. A BAC-transgenic (BTZIP8) mouse line containing 2 + 1 additional copies of the Slc39a8 gene shows a gene-dose-dependent increase in ZIPS mRNA in all tissues tested, and is acutely sensitive to Cd-induced kidney dysfunction. Slc39a8 is one of 14 members of a solute-carrier (SLC) family of metal transporters;Slc39a14 shares the most recent ancestry with Slc39a8;ZIP14 exists as two peptides, ZIP14A and ZIP14B, as a consequence of alternate exon splicing. The ZIP14s are expressed highest in small intestine and liver and have transport and toxicologic properties similar to ZIPS. Our hypothesis is that the ZIPS and ZIP14 transporters are the principal mediators of Cd-induced renal dysfunction. For the next funding period, we propose to: [1] characterize the transport and physiological properties of ZIPS, ZIP14A and ZIP14B in vitro;[2] study the physiological role of ZIPS in Cd-induced renal dysfunction using our BTZIP8 overexpresser and Slc39a8(-/-) knockout mouse models;and [3] develop and characterize similar mouse models for Slc39a14 These studies will improve our understanding of heavy-metal toxicity and may lead to uncovering new targets that might be useful for preventive strategies as well as therapeutic intervention in heavy-metal diseases.